1-alkyl-4-hydroxypiperidine esters



Patented May 9, 1950 ITED STATES 1=ALKYL=4 -HYDR-OXYPIPERIDINE ESTERSHenry Martin andAH-red Margot,sBasekSwitzer-?- land assignors :to' J. R.vGreigy; AeG Basel,

Switzerland 1 3 Claims. 12 This'application is a divisionoiiourcopendi'ng patent application Sr. No. 551,073, filedon August 24, 1944:

It s is I known: -.to resterif yj'4-hydroxypiperidmes (Cl. 260-:294.3) Z

2, Example 1 10.5 parts of .1 =phenyl-cyclopentyl-1 ecanboxylic acidchloride are added under stirring to 6 parts o11-ethyl-e-hydroxypiperidme and fthe mixture being substituted inl-position with .benzoicacid; 1 heated, hile further stirring =tr lfio9c for ands. with apeaminobenzoicc acid, wl-ierebye com pounds with localanesthetic eflects are obtained (er) Ain. S60: 51 922 11929! lricontradistinc tion thereto'--we"have-now found that esters ob tainable'from l-substituted =hydroxypiperidihes and 1 -aryl-cycloaliphatic-' 1carb'oxylicacids pos sess a surprising strong and manifest efiicacy onthe parasympathetic nervous system. Besides,

the said compounds are distinguished by minimal toxicity which is lowerthan that of the esters obtainable from corresponding acids and basicalcohols of the diethanol amine type, although the pronouncedneurotropic, atropine-like properties of the new compounds are by farincreased.

The basic esters claimed herein are water-soluble in form of their saltswith inorganic or organic acids.

The preparation of the esters is carried out in the usual manner, forinstance by causing reactive derivatives of thel-aryl-cycloaliphatic-l-carboxylic acids 1. e. their halides, esters oranhydrides to react with l-substituted 4-hydroxypiperidines in thepresence or absence of condensation agents or by causing reactive estersof the said hydroxypiperidines to react, in some cases in the presenceof acid binding agents, with the said acids or their salts respectively.

As reactive esters may be mentioned especially esters with hydrogenhalide acids, with aryl sulphonic acids and the like.

As aryl-substituted cycloaliphatic carboxylic acids being suitable forthe esterification may be mentioned for example: l-phenyl-cyclopropyl-l-4 carboxylic acid, l-phenyLl-cyclobutyl carboxylic acid,l-phenylcyclopentyl-l-carboxylic acid, 1- phenyl-cyclohexyll-carboxylicacid and so on. These acids and their halides may be prepared accordingto the method described in the Journal a short time, whereby withdevelopment of ,heat

a clear, bright -browzroi'l is produced'fwhlch, ad' vantageou'sly 1'when: still warm; is" treated with" water. The'aque'ous 'solution'is"extracted several times with ether and then the base isTreedby means ofconcentrated ammonia. The base is now extracted with ether .and,..afterhaving- 0nce washed and dried the ethereal solution, the solvent isdistilled'ofi-s The residue has a boiling point of IMP- C. at0.05:'mm-..=..pressure.

Example 2 20.8 parts of l-phenyl-cyclopentyl-l-carboxylic' acid chloridein 200 parts of chlorobenzene are treated, while stirring, with 12 partsof l-methyl- 4-hydroxypiperidine and the whole is subsequently heated toboiling for 2 hours. After cooling the mixture is extracted twice withwater and once with dilute hydrochloric acid. The combined aqueoussolutions are extracted with ether, the base is made free by means ofpotassium carbonate and extracted with ether. The ethereal solution iswashed with water, dried over potassium carbonate and the solvent isdistilled 011. The obtained 1-methyl-4-hydroxypiperidine ester ofl-phenyl-cyclopentyl-l-carboxylic acid boils at 139-140 C. under apressure of 0.05 mm. From this compound there may be obtained thehydrochloride melting at 179 C.

The following esters may be obtained in the same manner, when using thecorresponding acid chlorides: 1-methyl-4-hydroxypiperidine ester of1-(2'-methylphenyl) -cyclopentyl 1 carboxylic acid, B. P. 0.05 mm.133-135 C., and therefrom the hydrochloride melting at 152-153 C., 1-methyl-4=-hydroxypiperidine ester of1-(3'-methylphenyl)-cyclopentyl-l-carboxylio acid, B. P.

0.07 mm. 132-l34 C. and therefrom the hydrochloride melting at 187-188C., l-methyll-hydroxypiperidine ester ofl-(4'-methylphenyl)-cyclopentyl-l-carboxylic acid, B. P. 0.08 mm.134-136 C., and therefrom the hydrochloride melting at 241-22 C.,1-methyl-4-hydroxypiperidine ester of 1- (3' :4'-dimethylphenyl)-cyc1opentyl l-carb0xy1ic acid, B. P. 0.05 mm. 143144 C., and there-Instead of the chlorides used in the above ex amples also other halidesor the corresponding anhydrides or reactive esters may be used. Insteadof the carboxylic acids and hydroxypiperidines used in the aboveexamples also the other compounds enumerated in the introductory part ofthis specification can be used. Most of the cited carboxylic acids areknown; where this is not the case, the same can be prepared according tothe methods which are usual for the known acids.

What we claim is:

1. A 1-alky1-4-hydroxypiperidine ester of the formula wherein Ar standsfor a member selected from the group consisting of phenyl andmethylphenyl. '2. An ester of 1-alky1-4-hydroxypiperidine of 4 3. Anester of 1-alky1-4-hydroxypiperidine of the formula G a CH:

HENRY MAR'I'IN. ALFRED MARGOT.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS GHa-CH:

N-CH:

CHr-C Number Name Date 2,265,184 Mieicher et al. Dec. 9, 1941 2,370,114Klemme et a1. Feb. 20, 1945 2,387,879 Burtner Oct. 30, 1945 FOREIGNPATENTS Number Country Date 92,589 Germany May 24, 1897 483,258 GreatBritain Apr. 14, 1938 532,943 Great Britain Feb. 4, 1941 60,592 DenmarkFeb. 15, 1943 OTHER REFERENCES Case, Jour. Amer. Chem. $00., vol. 56(1934),

80 pages 715-717.

Halpern, Comp, Rend., vol. 126, pages 678 and 679 (1937).

Halpern, Arch int de Pharmacodyn et de Therapie, v01. 59 (1938, pages149-151) Burtner et al., Jour. Amer. Chem. Soc, vol. 65, pages 262-267(Feb. 1943).

1. A 1-ALKYL-4-HYDROXPIPERIDINE ESTER OF THE FORMULA WHEREIN AR STANDSFOR A MEMBER SELECTED FROM THE GROUP CONSISTING OF PHENYL ANDMETHYLPHENYL.